Fig. 1.

Type I and type III IFN signal transduction pathways. Viral nucleic acids are recognized by transmembrane TLRs, cytoplasmic DNA sensors and RNA helicases, leading to the activation of kinases. These kinases promote the activation of the NF-κB, IRF3 and IRF7 transcription factors and their subsequent translocation to the nucleus where they stimulate IFN gene transcription. IFN-λ1 and IFN-β gene expression largely depends on IRF3 and NF-κB. Expression of IFN-λ2 and IFN-λ3, like that of IFN-α, depends more on IRF7 availability. Type I IFNs use a dimeric receptor composed of IFNAR1 and IFNAR2c. Type III IFNs signal through a different receptor, which is composed of IFNLR1 and IL10RB. Upon binding to their cognate receptors, type I and type III IFNs induce the same Jak/STAT pathway: the transphosphorylation and activation of receptor-associated Jak1 and Tyk2 leads to the phosphorylation of STAT1 and STAT2 transcription factors. Phosphorylated forms of STAT1 and STAT2 further associate with IRF9 to form a heterotrimeric ISG factor 3 (ISGF3) complex. ISGF3 then translocates to the nucleus where it binds to sequences of IFN-stimulated response elements present in the promoter of ISGs to upregulate their transcription. Some ISG products participate themselves in the signaling pathways leading to IFN production and IFN responses thus creating positive (and negative) feedback loops. Given the similarity of type I and type III IFN pathways, IFN-λ is expected to influence both the production of and response to IFN-α/β, and vice versa. cGAS = Cyclic GMP-AMP synthase.